FDA Turns Down MS Drug Lemtrada

by John Gever John Gever,Deputy Managing Editor, MedPage Today
December 30, 2013

The FDA has told Sanofi's Genzyme unit that it would not approve alemtuzumab (Lemtrada) for multiple sclerosis until the firm performs another trial with an active comparator.

According to a statement issued by Sanofi, "FDA has taken the position that Genzyme has not submitted evidence from adequate and well-controlled studies that demonstrate the benefits of Lemtrada outweigh its serious adverse effects.

"Genzyme understands that the conclusion is related to the design of the completed Phase 3 active comparator studies of Lemtrada in relapsing-remitting MS patients. FDA has also taken the position that one or more additional active comparator clinical trials of different design and execution are needed prior to the approval of Lemtrada."

The company said it strongly disagreed with the FDA's decision and vowed to appeal it.

The European Union approved the drug in September. More recently, authorities in Australia and Canada followed suit.

Alemtuzumab targets the CD52 immune cell surface protein, depleting certain classes of cells and inducing a long-lasting reshuffle in the immune-cell mix. The clinically relevant result is a down-regulation of inflammatory activity in MS.

The drug's mechanism of action allows it to be given very infrequently -- in an initial 5-day course of infusions, followed by a second 3-day course a year later.

Key to the decision was Genzyme's two pivotal trials. Called CARE MS I and CARE-MS II, the studies pitted the drug against beta-interferon, a standard drug for relapsing-remitting MS.

The results generally showed that alemtuzumab was superior to interferon in reducing relapses, with some evidence as well that it reduced progression of disability. Progression was significantly slower in one of the trials but the effect failed to show statistical significance in the other.

In November, an FDA advisory committee determined that alemtuzumab was effective for reducing relapses and that its safety issues should not preclude approval. But panel members also found that the drug's effect against disability progression remained unproven.

FDA staff members had told the committee that they had strong reservations about the rigor of the clinical trials. Because Genzyme wanted to use an active control that required frequent dosing, a double-blind trial was not feasible. Instead, both CARE-MS studies were conducted on an open-label basis. The drug's safety was also a major concern, the reviewers said.

Neurologists contacted by MedPage Today prior to the FDA's announcement expressed hope that the agency would clear the drug for MS.

"While there are very valid concerns about the data interpretation from the trial and safety profile of the drug, there are reasonable levels of efficacy data to support its approval," said Benjamin Greenberg, MD, of the University of Texas Southwestern Medical Center in Dallas, in an email.

"Given its unique and profound mechanism of action, this drug will have potential uses for specific patients who have the highest need for efficacious interventions."

Neil Lava, MD, of Emory University in Atlanta, agreed. "Most of the neurologists in the MS community want this medication to be approved. It will be an excellent addition to our MS drug armamentarium," he said.

Both men said that the drug's autoimmune side effects are a serious issue, however, requiring that patients in routine practice be monitored and that studies evaluate the risk more carefully.

"A very intense postmarketing surveillance program would be extremely useful for formulating long-term assessments of this medication," Greenberg said.

Following the FDA’s decision, Robert Bermel, MD, of the Cleveland Clinic, who helped lead the drug’s pivotal trials, told MedPage Today that it was disappointing but the community could cope with it.

“Though it would be preferred to have alemtuzumab available as a treatment option in the U.S. as it is in Canada, the European Union, and Australia, I am optimistic that in the U.S. we can still find a treatment option to fit just about any patient with MS,” he said in an email.

Alemtuzumab had shaped up to be the last really novel treatment for MS to come along for a while.

Over the past decade, treatment options for MS expanded tremendously. The first two specific MS treatments, interferon-beta (Avonex, Betaseron, Rebif) and glatiramer acetate (Copaxone) were approved in the 1990s. Then the range of options exploded beginning in 2004 with the approval of natalizumab followed by the oral drugs fingolimod (Gilenya), teriflunomide (Aubagio), and, most recently, dimethyl fumarate (Tecfidera).

But no others with mechanisms of action differing from these agents are expected to win approval any time soon.

The only such drug in the late-stage pipeline, laquinimod, has been stalled since 2011, when it failed to meet its primary endpoint in a phase III trial. The FDA reportedly told laquinimod's developers to conduct another phase III trial before it would consider approving the drug. Such a trial began enrolling patients in March of this year, with disability progression as the primary outcome.

Jeffrey Cohen, MD, also of the Cleveland Clinic, told MedPage Today in an email that the field is moving in other directions now.

The next clinically relevant developments are likely to be "what I consider improvements of current therapies," he wrote, such as new interferon-based drugs with longer half-lives in circulation and agents similar to fingolimod but with greater target selectivity.

"Beyond anti-inflammatory strategies, I see increasing emphasis on the development of neuroprotective and repair promoting strategies which probably will be necessary to treat progressive disease, in particular," he added.

But Cohen, a principal investigator in the alemtuzumab trials, also said that the "anti-inflammatory" approach had not yet been exhausted. He indicated that biologic agents targeting specific immune cell classes -- the anti-CD25 drug daclizumab (Zenepax) and the B-cell depleting agent ocrelizumab -- also were promising for MS.

Alemtuzumab had previously been sold under the name Campath as a treatment for B-cell leukemias. After gaining rights to the drug, Sanofi took it off the market for that purpose, because the firm didn't want it prescribed off-label for MS. The company is still providing it to leukemia patients who had started on it earlier and continue to do well.

UPDATE: This article, originally published Dec. 30, 2013, at 9:45 a.m., was updated with new material Dec. 30, 2013, at 5:40 p.m.).